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Among epithelial ovarian cancer, clear cell carcinoma is common for chemo-resistance and high mortality. This cancer arises from benign ovarian endometrioma (OE), which is a high oxidative stress environment due to the cystic retention of menstrual blood produced during menstruation and the "iron" liberated from the cyst. There has been strong evidence that the iron concentration in OE decreases when they become cancerous. A decrease in iron concentration is a necessary condition for the formation of cancer. However, the mechanism of carcinogenesis is not yet clear. In the current study, the bacterial flora in endometriosis-associated ovarian cancer (EAOC), including clear cell carcinoma, and their origin, OE, were investigated using next-generation sequencing. The Shannon index in the genus level was significantly higher in EAOC than in OE fluids. Among several bacterial flora that were more abundant than benign chocolate cysts, a number of bacterial species that correlate very well with iron concentrations in the cysts were identified. These bacterial species are likely to be associated with decreased iron concentrations and cancer development.

Intermittent hypoxia (IH) is a central characteristic of sleep apnea syndrome (SAS), and it subjects cells in the body to repetitive apnea, chronic hypoxia, oxygen desaturation, and hypercapnia. Since SAS is linked to various serious cardiovascular complications, especially hypertension, many studies have been conducted to elucidate the mechanism of hypertension induced by SAS/IH. Hypertension in SAS is associated with numerous cardiovascular disorders. As hypertension is the most common complication of SAS, cell and animal models to study SAS/IH have developed and provided lots of hints for elucidating the molecular mechanisms of hypertension induced by IH. However, the detailed mechanisms are obscure and under investigation. This review outlines the molecular mechanisms of hypertension in IH, which include the regulation systems of reactive oxygen species (ROS) that activate the renin-angiotensin system (RAS) and catecholamine biosynthesis in the sympathetic nervous system, resulting in hypertension. And hypoxia-inducible factors (HIFs), Endotheline 1 (ET-1), and inflammatory factors are also mentioned. In addition, we will discuss the influences of SAS/IH in cardiovascular dysfunction and the relationship of microRNA (miRNA)s to regulate the key molecules in each mechanism, which has become more apparent in recent years. These findings provide insight into the pathogenesis of SAS and help in the development of future treatments.

The tissue factor pathway inhibitor-2 (TFPI2) was recently identified as a diagnostic serum marker for ovarian clear cell carcinoma. Moreover, the immunohistochemical expression of TFPI2 in ovarian clear cell carcinoma was recently reported. This single-center retrospective study aimed to evaluate whether TFPI2 can be a specific biomarker for immunohistological diagnosis of endometrial clear cell carcinoma (ECCC). Immunohistochemical staining of TFPI2 in 55 endometrial carcinomas was evaluated at Nara Medical University Hospital. Thirteen ECCC samples were included as cases and 42 samples were included as a control (endometrioid carcinoma grade 1, 11 cases; grade 2, 11 cases; grade 3, 10 cases; serous carcinoma, 10 cases). The mean ± SD TFPI2 histoscore for diagnosing ECCC was 115.4 ± 87.9, which was significantly higher than that of non-ECCC (21.3 ± 45.9, P = 0.002). The best TFPI2 histoscore value obtained from the analyses of receiver operating characteristic curves for immunohistochemical diagnosis of ECCC was 15. With TFPI2 histoscores ≥15.0 as positive and <15.0 as negative, all 13 ECCC cases (100%) were positive for TFPI2, whereas 11 (26.2%) non-ECCC cases were positive for TFPI2. The sensitivity and specificity of TFPI2 for diagnosing ECCC were 100% and 73.8%, respectively. TFPI2 is expressed in ECCC and is useful for histopathological diagnosis., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 by the International Society of Gynecological Pathologists.)

Abundant intrauterine Lactobacillus is associated with good in vitro fertilization (IVF) outcomes; however, whether specific species of Lactobacillus have any benefit remains unclear. So we examine the effect of Lactobacillus on the clinical outcomes of IVF at the species level. Uterine microbiota were classified as either Lactobacillus-dominant (LD) or non-Lactobacillus-dominant. In the LD group, we further investigated the clinical results for each Lactobacillus species and evaluated them in relation to IVF outcomes. In Uterine microbiome analysis, Lactobacillus was the most abundant, with the four species of L. crispatus, L. iners, L. gasseri, and L. jensenii accounting for the great majority. We compared the clinical outcomes of single frozen-thawed embryo transfer conducted by Lactobacillus species and found that the implantation rate was lowest in those in whom L. iners was dominant. This study is the first to conduct a species-level analysis of the uterine microbiota and report on a detailed investigation of Lactobacillus, which was believed to be particularly helpful for pregnancy., Competing Interests: Declaration of Competing Interest I have the following conflicts of interest: none., (Copyright © 2023. Published by Elsevier B.V.)

Advanced endometrial cancer (EC) often recurs and has a poor prognosis. Various serum markers have been used for EC but their usefulness as biomarkers is still unclear; therefore, identifying new biomarkers is important. The present study aimed to investigate whether the tissue factor pathway inhibitor-2 (TFPI2) level was elevated in the preoperative serum of patients with EC and if it may be a prognostic factor. The present retrospective study included 207 patients who had a confirmed pathological diagnosis of EC and received surgical therapy as the initial treatment between January 2011 and December 2017. Survival analysis was performed using Kaplan-Meier analysis and the Cox proportional hazards regression model. The 5-year disease-free survival and overall survival (OS) rates were 73.3 and 83.7%, respectively. The cut-off value for predicting OS for TFPI2 level was 177 pg/ml as determined from the receiver operating characteristic curve. A TFPI2 value ≥177 pg/ml was significantly associated with age ≥65 years (P<0.001), diabetes (P=0.035), stage (P<0.001), myometrial invasion (P<0.001), lymphovascular invasion (P=0.004), lymph node metastasis (P=0.010), distant metastasis (P<0.001), cancer antigen (CA) 125 ≥36 U/ml (P<0.001) and CA 19-9 ≥38 U/ml (P<0.001). In multivariate analysis, high-grade carcinoma [hazard ratio (HR), 2.439; P=0.041], lymph node metastasis (HR, 2.116; P=0.038), distant metastasis (HR, 3.604; P=0.009) and TFPI2 level ≥177 pg/ml (HR, 2.42; P=0.043) were significant prognostic factors affecting OS in patients with EC. These results suggest that the preoperative serum TFPI2 level, along with its histological type, lymph node metastasis and distant metastasis, was a prognostic factor for OS in patients with endometrial cancer., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2023, Spandidos Publications.)

Objective: This study aimed to verify the utility of simple, safe, and effective venous thromboembolism (VTE) prophylaxis and implement it with few adverse events during cesarean delivery., Methods: This single-center, prospective study involved pregnant women who underwent cesarean deliveries from August 3, 2020 to March 31, 2022. Patients with VTE risk factors were initially administered unfractionated heparin (5,000 international unit [IU] subcutaneously, twice daily), 6 hours after cesarean delivery. Subsequently, they were administered enoxaparin (2,000 IU subcutaneously, twice daily). They were not administered anticoagulants if one or more of the exclusion criteria were met. The primary efficacy outcome was the incidence of symptomatic VTE. The primary safety outcome was the incidence of major bleeding., Results: Out of the 850 women eligible for this study, 551 (64.9%) had one or more VTE risk factors and 299 (35.1%) had no risk factors. Of the 551 women with one or more VTE risk factors, 15 met one or more exclusion criteria for enoxaparin administration. A total of 314 women received only perioperative mechanical prophylaxis, including 15 who met the exclusion criteria for anticoagulants and 299 without VTE risk factors. During implementation of the protocol, no woman developed symptomatic VTE after cesarean delivery. Major bleeding occurred in only one woman who received postoperative anticoagulants., Conclusion: This protocol, which clarified the administration of anticoagulants according to VTE risk factors and dose reduction/discontinuation criteria, may be an effective and safe VTE prophylaxis for cesarean deliveries.

Endometriosis is a disease that is characterized by the ectopic presence of the endometrium or its similar cells. A high prevalence of patients with autoimmune diseases has been reported among patients with endometriosis although the cause of endometriosis remained unknown. Recently, the anti-lactoferrin antibody is reported to be highly detected in autoimmune diseases. This study focused on lactoferrin and anti-lactoferrin antibodies to explore the pathology of endometriosis. Lactoferrin is a substance that regulates inflammation and is produced by neutrophils. Anti-lactoferrin antibody is a type of perinuclear antineutrophil cytoplasmic antibody. The serum lactoferrin and anti-lactoferrin antibody levels were compared among patients with or without endometriosis, revealing significantly higher levels in patients with endometriosis. Additionally, a decreased serum anti-lactoferrin antibody level was observed after surgical endometriosis resection. The receiver operating characteristic curve analysis determined the reference values for the serum lactoferrin and anti-lactoferrin antibody levels. Patients whose serum level exceeded the reference anti-lactoferrin antibody value were significantly higher in more than 40% of cases in the endometriosis group. The rate is comparable to that of autoimmune diseases. This is the first report that anti-lactoferrin antibody is frequently observed in patients with endometriosis, adding a new perspective to the understanding of the pathology of endometriosis although precisely elucidating the mechanism by which lactoferrin and anti-lactoferrin antibody appear in endometriosis in the future is necessary.

Chronic endometritis (CE) is a type of chronic inflammation in the endometrium that is associated with infertility, which is primarily due to implantation failure. Antibiotics are the most common treatment for CE. However, some patients with CE are resistant to antibiotic treatment, while others refuse this treatment. Therefore, we focused on lactoferrin (Lf), which exhibits antimicrobial and anti-inflammatory properties, and studied its effect on inflammation in endometrial stromal cells (ESCs) from patients with CE. Endometrial tissue was collected from patients with CE, and ESCs were isolated and cultured. When ESCs were cultured with bovine lactoferrin (bLf: 1 mg/mL), the mRNA expression of TNF-α (p < 0.05) and IL-1β (p < 0.01) was significantly decreased compared with that in cells cultured without bLf. The level of TNF-α protein in the culture medium was significantly decreased (p < 0.01), while that of IL-1β was also decreased, but not significantly (p < 0.10), when 1 mg/mL of bLf was added to the culture medium. When more inflammation was induced artificially by adding 0.1 ng/mL of TNF-αto ESCs, the addition of bLf (1 mg/mL) to ESCs decreased IL-6 and IL-1β mRNA expression to levels similar to those in ESCs without TNF-α treatment. Furthermore, it was revealed that the actions of bLf are mediated by the AKT and MAPK intracellular signaling pathways, which are mechanisms by which the increase in TNF-α-induced cytokine expression is suppressed in ESCs. bLf suppresses the expression of inflammatory cytokines in human ESCs and may be a new therapeutic candidate for CE., Competing Interests: Declaration of Competing Interest None of the authors has any conflict of interest related to this manuscript., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Magnetic resonance (MR) relaxometry provides a noninvasive tool to discriminate endometriosis-associated ovarian cancer (EAOC) from ovarian endometrioma (OE) with high accuracy. However, this method has a limitation in discriminating malignancy in clinical use because the R2 value depends on the device manufacturer and repeated imaging is unrealistic. The current study aimed to reassess the diagnostic accuracy of MR relaxometry and investigate a more powerful tool to distinguish EAOC from OE., Methods: This retrospective study was conducted at our institution from December, 2012, to May, 2022. A total of 150 patients were included in this study. Patients with benign ovarian tumors ( n = 108) mainly received laparoscopic surgery, and cases with suspected malignancy ( n = 42) underwent laparotomy. Information from a chart review of the patients' medical records was collected., Results: A multiple regression analysis revealed that the age, the tumor diameter, and the R2 value were independent malignant predicting factors. The endometriotic neoplasm algorithm for risk assessment (e-NARA) index provided high accuracy (sensitivity, 85.7%; specificity, 87.0%) to discriminate EAOC from OE., Conclusions: The e-NARA index is a reliable tool to assess the probability of malignant transformation of endometrioma., Competing Interests: The authors declare no conflict of interest.

Pregnancy causes changes in the uterus, such as increased cell volume and altered water content. However, the mechanisms that protect the structure and maintain the function of uterine smooth muscle cells against these changes during pregnancy have not been clarified. This study focused on the volume-regulated anion channel (VRAC), which opens with cell swelling under low osmotic pressure and releases Cl - ions and various organic osmolytes to resist cell swelling and regulates a wide range of biological processes such as cell death. In this study, myometrial smooth muscle (MSM) tissues and cells (MSMCs) were collected from non-pregnant and pregnant mice. Using western blotting and immunocytochemistry, leucine-rich repeat containing protein 8A (LRRC8A), an essential membrane protein that constitutes part of the VRAC, was determined to be diffused throughout MSMCs including in the cell membrane. Patch-clamp experiments were performed to investigate the electrophysiology of swelling-induced Cl - currents (I Cl, swell ) mediated by the VRAC. No significant changes between non-pregnancy and pregnancy groups were observed in either the expression density of LRRC8A or the current density of I Cl, swell , however the presence of LRRC8A on the cell membrane was significantly increased in the third trimester of pregnancy compared to the non-pregnancy. This study suggests that the VRAC may play a role, such as maintaining cellular homeostasis in the pregnant MSM.

The Japan Society of Clinical Oncology (JSCO) published the "JSCO Clinical Practice Guidelines 2017 for Fertility Preservation in Childhood, Adolescent, and Young Adult Cancer Patients" in 2017. This was the first guideline in cancer reproductive medicine in Japan. In the field of cancer reproductive medicine, close cooperation between an oncologist and a physician for reproductive medicine is important from before treatment initiation until long after treatment. The guideline takes into consideration disease specificity and provides opinions from the perspective of oncologists and specialists in reproductive medicine that are in line with the current state of the Japanese medical system. It is intended to serve as a reference for medical staff in both fields regarding the availability of fertility preservation therapy before the start of cancer treatment. Appropriate use of this guideline makes it easier to determine whether fertility preservation therapy is feasible and, ultimately, to improve survivorship in childhood, adolescent, and young adult cancer patients. In this article (Part 2), we describe details by organ/system and also for pediatric cancer., (© 2021. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

In 2017, the Japan Society of Clinical Oncology (JSCO) published the JSCO Clinical Practice Guidelines 2017 for Fertility Preservation in Childhood, Adolescent, and Young Adult Cancer Patients. These were the first Japanese guidelines to address issues of oncofertility. In this field of medicine, sustained close cooperation between oncologists and reproductive specialists is essential from the diagnosis of cancer until many years after completion of cancer treatment. These JSCO guidelines were intended to guide multidisciplinary medical staff in considering the availability of fertility preservation options and to help them decide whether to provide fertility preservation to childhood, adolescent, and young adult cancer patients before treatment starts, with the ultimate goal of improving patient survivorship. The guidelines are presented as Parts 1 and 2. This article (Part 1) summarizes the goals of the guidelines and the methods used to develop them and provides an overview of fertility preservation across all oncology areas. It includes general remarks on the basic concepts surrounding fertility preservation and explanations of the impacts of cancer treatment on gonadal function by sex and treatment modality and of the options for protecting/preserving gonadal function and makes recommendations based on 4 clinical questions. Part 2 of these guidelines provides specific recommendations on fertility preservation in 8 types of cancer (gynecologic, breast, urologic, pediatric, hematologic, bone and soft tissue, brain, and digestive)., (© 2021. The Author(s).)

Purpose: To explore the histopathological findings of cesarean scar defect (CSD) and the immunological component in women with cesarean scar syndrome (CSS)., Methods: This retrospective study was conducted in a university hospital and a public hospital. A total of 63 patients with secondary infertility due to CSS who underwent laparoscopic resection of the CSD lesion were enrolled (CSS group), and 21 patients who underwent hysterectomy with a history of cesarean section were enrolled as control (non-CSS group). We compared the differences in histopathological findings of CSD lesions by hematoxylin and eosin staining and immunohistochemistry for CD3, CD20, CD56, CD68, CD138, myeloperoxidase, and tryptase between the two groups., Results: The frequency of presence of endometrium on the CSD surface was significantly lower ( p  = 0.0023) and that of adenomyosis was significantly higher ( p  = 0.0195) in the CSS group than in the non-CSS group. The number of CD3-, CD20-, CD68-, and tryptase-positive cells was significantly lower in the CSS group than in the non-CSS group; however, the number of CD138-positive cells was significantly higher in the CSS group ( p  = 0.0042)., Conclusions: This study suggested that the absence of endometrium, presence of adenomyosis, and chronic inflammation in CSD contributes to secondary infertility due to CSS., Competing Interests: Asuka Higuchi, Shunichiro Tsuji, Yuri Nobuta, Akiko Nakamura, Daisuke Katsura, Tsukura Amano, Fuminori Kimura, Satoshi Tanimura, and Takashi Murakami declare that they have no conflict of interest., (© 2021 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.)

Ultrasonography and fetal heart rate monitoring are subjective assessments of fetal condition, which warrants the need for objective markers to predict fetal condition. Urinary L-type fatty acid-binding protein (L-FABP) levels correlate with hypoperfusion. Elevated amniotic fluid L-FABP levels may represent fetal tissue hypoperfusion since the amniotic fluid contains fetal urine. In this study, we aimed to analyze the effectiveness of amniotic fluid L-FABP as a predictor of fetal condition. We classified singleton pregnancies into groups based on fetal growth restriction (FGR) with and without fetal blood flow abnormalities (FGR and healthy-FGR groups, respectively) and the non-FGR group (control group). We collected amniotic fluid at the time of vaginal delivery, cesarean section and amniocentesis, and compared the patient characteristics, clinical outcomes and amniotic fluid levels of L-FABP between the groups. We analyzed 153 singleton pregnancies and 186 amniotic fluid samples (FGR group, 6 (3.9%) pregnancies and 23 (12.4%) samples; healthy-FGR group, 15 (9.8%) pregnancies and 20 (10.7%) samples; control group, 132 (86.3%) pregnancies and 143 (76.9%) samples). The amniotic fluid L-FABP level was significantly higher in the FGR group compared to that in the healthy-FGR and control groups. Multivariate analysis revealed that the amniotic fluid L-FABP level was not affected by fetal body weight. Additionally, the amniotic fluid L-FABP levels increased significantly in cases with fetal blood flow abnormalities or early gestational age. Therefore, amniotic fluid L-FABP level may be an objective and accurate predictive marker of fetal condition.

Osteogenesis imperfecta (OI), or brittle bone disease, is a heterogeneous disorder characterised by bone fragility, multiple fractures, bone deformity, and short stature. OI is a heterogeneous disorder primarily caused by mutations in the genes involved in the production of type 1 collagen. Severe OI is perinatally lethal, while mild OI can sometimes not be recognised until adulthood. Severe or lethal OI can usually be diagnosed using antenatal ultrasound and confirmed by various imaging modalities and genetic testing. The combination of imaging parameters obtained by ultrasound, computed tomography (CT), and magnetic resource imaging (MRI) can not only detect OI accurately but also predict lethality before birth. Moreover, genetic testing, either noninvasive or invasive, can further confirm the diagnosis prenatally. Early and precise diagnoses provide parents with more time to decide on reproductive options. The currently available postnatal treatments for OI are not curative, and individuals with severe OI suffer multiple fractures and bone deformities throughout their lives. In utero mesenchymal stem cell transplantation has been drawing attention as a promising therapy for severe OI, and a clinical trial to assess the safety and efficacy of cell therapy is currently ongoing. In the future, early diagnosis followed by in utero stem cell transplantation should be adopted as a new therapeutic option for severe OI.

Background: The diagnostic criteria of chronic endometritis remain controversial in the treatment for infertile patients., Methods: A prospective observational study was conducted in a single university from June 2014 to September 2017. Patients who underwent single frozen-thawed blastocyst transfer with a hormone replacement cycle after histological examination for the presence of chronic endometritis were enrolled. Four criteria were used to define chronic endometritis according to the number of plasma cells in the same group of patients: 1 or more (≥ 1) plasma cells, 2 or more (≥ 2), 3 or more (≥ 3), or 5 or more (≥ 5) in 10 high-power fields. Pregnancy rates, live birth rates, and miscarriage rates of the non-chronic endometritis and the chronic endometritis groups defined with each criterion were calculated. A logistic regression analysis was performed for live births using eight explanatory variables (seven infertility factors and chronic endometritis). A receiver operating characteristic curve was drawn and the optimal cut-off value was calculated., Results: A total of 69 patients were registered and 53 patients were finally analyzed after exclusion. When the diagnostic criterion was designated as the presence of ≥ 1 plasma cell in the endometrial stroma per 10 high-power fields, the pregnancy rate, live birth rate, and miscarriage rate were 63.0% vs. 30.8%, 51.9% vs. 7.7%, and 17.7% vs. 75% in the non-chronic and chronic endometritis groups, respectively. This criterion resulted in the highest pregnancy and live birth rates among the non-chronic endometritis and the smallest P values for the pregnancy rates, live birth rates, and miscarriage rates between the non-chronic and chronic endometritis groups. In the logistic regression analysis, chronic endometritis was an explanatory variable negatively affecting the objective variable of live birth only when chronic endometritis was diagnosed with ≥ 1 or ≥ 2 plasma cells per 10 high-power fields. The optimal cut-off value was obtained when one or more plasma cells were found in 10 high-power fields (sensitivity 87.5%, specificity 64.9%)., Conclusions: Chronic endometritis should be diagnosed as the presence of ≥ 1 plasma cells in 10 high-power fields. According to this diagnostic criterion, chronic endometritis adversely affected the pregnancy rate and the live birth rate.

A number of scholarly reports have shown the importance of mental health care during pregnancy, especially for women with mental disorders. Nevertheless, the postpartum mortality rate due to mental disorders has been a serious issue in Japan. Therefore, since January 2015, our hospital has implemented a liaison system in which one psychiatric nurse specialist contributes to perinatal care. The aim of this study is to explore the impacts of a psychiatric nurse specialist as a liaison for pregnant women with mental disorders. More specifically, the investigation was retrospectively performed from January 2011 to December 2019 using medical records from a single university medical hospital in Japan. Participants comprised pregnant women with mental disorders. Of the 4,066 total deliveries completed during the study period, 152 women were detected as being exposed to the liaison system (2015-2019), while 92 were recognized as controls (2011-2014). We then conducted a comparative analysis between those who were exposed to the liaison system and the control group. Except for Apgar scores taken five minutes after birth, there were no intergroup differences in the patient characteristics or perinatal psychiatric outcomes. We found that the liaison system was associated with an increased rate of referral to the local public health center (p = 0.003). The system also significantly delayed the time at which patients first visited a psychiatrist because a psychiatric nurse could determine the urgency through interviews with the patients. Overall, our results suggest that the liaison system is helpful for pregnant women with mental disorders.

Objectives: Fertility preservation is important for Children, Adolescent and Young Adult(CAYA)cancer patients. Although a regional oncofertility network was established in Japan in 2012, regional inequality persists. This study was aimed at expanding the oncofertility network throughout Japan., Methods: Oncologists, reproductive medicine specialists, and administrative officials from 24 regions, currently without a regional oncofertility network, conferred to discuss problems and strategies for network expansion., Results: Regional oncofertility networks had already been established in 4 of 24 regions. Consultation and support and a collaboration system between facilities and individual doctors were found in 13 and 14 regions, respectively. Regarding which organization should lead the network operation, the regions(number)chose the prefecture (10), prefectural cancer centers(10), and OB/GYN department of hospitals specializing in cancer treatment(9). Obstacles to establishing a regional oncofertility network were the lack of manpower(21), budget(19), know-how(16), and specialists( 12)., Discussion: CAYA cancer patients need equal access to oncofertility networks, and a public support system is essential for preserving the fertility of cancer patients. We should organize a oncofertility network in association with prefectural administration. Medical staff training and supply of materials using the Oncofertility Consortium Japan system are required to promote the oncofertility network throughout Japan.

Eating disorders are common psychiatric disorders among women of reproductive age, and the prevalence of eating disorders has been increasing over time in Japan and other countries. The aim of the present study was to assess perinatal outcomes in maternal anorexia nervosa in Japan and to explore methods to improve perinatal outcomes. This study consists of a case series describing 13 single pregnancies of 11 women with a history of anorexia nervosa, and a cross-sectional study comparing 13 cases with 240 healthy controls. In the case group, nine cases conceived while underweight, including three who had fertility treatment. Anorexia symptoms during pregnancy were quite common, and pregnant smokers presented with extremely disturbed eating behaviors. In a cross-sectional study, premature birth and the standard deviations from the mean birth weight and mean head circumference at birth were evaluated as outcome measures. The adjusted odds ratios or the adjusted differences between two means for the above outcomes were estimated by two approaches: multivariate models and matching analysis. Statistical analysis showed that maternal anorexia nervosa was associated with an increased risk of premature birth and symmetric growth restriction mediated by low pre-pregnancy body mass index and poor gestational weight gain which were adjusted as confounders. Smoking during pregnancy was a potential indicator of abnormal eating behavior and could be predictive of poor perinatal outcomes. We therefore conclude that remission of anorexia nervosa before pregnancy could improve perinatal outcomes through both normal nutrition and smoking cessation. Fertility treatment while underweight is not recommended.

Background: Adenomyosis is a benign gynecological condition in which endometrial tissue or endometrial-like tissue develops within the uterine myometrium. Few cases of disseminated intravascular coagulation has been reported in the patients with adenomyosis. Although hysterectomy is indicated for refractory massive uterine bleeding in the patients with advanced uterine adenomyosis, conservative treatment is often desired in women in the late reproductive age. Recently such cases are increasing due to the social trend of late marriage., Case Presentation: A 37-year-old woman with huge adenomyosis, gravida 2 para 0, was referred to our hospital to terminate her pregnancy. Acute, non-septic, disseminated intravascular coagulation (DIC) developed after early pregnancy was terminated in a woman with huge adenomyosis. Massive bleeding and DIC occurred 3 days after the dilatation and curettage. There was no evidence of infection as the cause of the DIC, because neither bacteria nor endotoxin could be detected in her blood, and antithrombin 3 (AT3), which would be expected to decrease in septic patients, was not decreased. Hemorrhage in the adenomyotic tissue after the termination presumably developed inflammation, with numerous microthrombi and necrosis in the adenomyotic tissue, which subsequently promoted coagulation and fibrinolysis, leading to the onset of massive uterine bleeding and DIC. Although severe hyperfibrinolysis is observed in peripheral blood, the fibrinolysis state in the uterine myometrium is considered to be even more severe. The newly formed clots for hemostasis under the uterine mucosa could be removed due to the excessive activation of fibrinolytic system happened in the adjacent myometrium, leading to the onset of massive uterine bleeding. Massive bleeding and DIC resolved quickly after the patient was treated with nafamostat mesilate, which is effective for both excessive coagulation and fibrinolysis., Conclusions: Adenomyosis could cause massive bleeding and DIC when pregnancy is terminated. Massive bleeding was considered to occur because the excessive fibrinolysis system inside adenomyosis affected the adjacent endometrium. Before considering hysterectomy to control refractory uterine bleeding, nafamostat mesilate should be considered as one option, thinking the pathophysiology of the massive bleeding due to uterine adenomyosis.

The uterus is an organ for raising the fetus, and its lumen is lined by the endometrium. The endometrium is an important site for the implantation and maturation of fertilized eggs. The endometrium undergoes repetitive proliferation, maturation (decidualization), and exfoliation changes every menstrual cycle. At the same time, the number and type of endometrial immunocompetent cells vary during the menstrual cycle. At the implantation stage, the immunocompetent cells occupy approximately half of the endometrial cells. Immunocompetent cells normally eliminate pathogenic microorganisms to protect the body; however, they also promote immune tolerance to accept the fetus during pregnancy. The immunocompetent cells in the uterus can perform both these functions. With the establishment of pregnancy, stimuli from the trophoblast (placenta) and fetus can also change the immune environment of the uterus, and pregnancy can be maintained only when the immune system is well adapted to the stimuli of some hormones and the fetus. Immunity for the establishment of pregnancy is not simple because multiple immunocompetent cells are involved in establishing and maintaining pregnancy. To understand the immune mechanisms associated with the establishment of pregnancy, we have to learn about each immune cell. This review, therefore, discusses the roles and distribution of the immunocompetent cells inside the uterus during menstruation and early pregnancy.

A national survey conducted in 2016 aimed to evaluate the current status and needs of the field of oncofertility and to consider optimized medical delivery systems. A total of 739 oncologists, excluding gynecological and urological specialists, were surveyed. Of these, 99.2% thought that providing information on fertility preservation was important. Of the surveyed oncologists, 48% were affiliated with facilities providing assisted reproductive technology, and 79.3% practiced in university hospitals. Of 238 (32.2%) specialists who provided information on the risk of reproductive damage resulting from treatment in their facility, 163 (44.9%) and 75 (19.9%) practiced in university hospitals (n=363) and non-university hospitals (n= 376), respectively. In contrast, 14.3% and 32.7% of oncologists who practiced in university hospitals and non-university hospitals, respectively, collaborated with local obstetricians and gynecologists. Among oncologists who use a gradually expanding regional oncofertility network, 0.6% practice in university hospitals and 2.7% practice in non-university hospitals. Patients were advised that the risk of infertility was 92.3% and the likelihood of fertility preservation was 66.9%. Furthermore, as an ideal way of providing information on preservation of fertility, 22.9% of oncologists collaborate with local gynecologists, and 26.3% do so at a public cancer and reproductive medical counseling center. In addition, 34.7% and 55.1% of oncologists at university and non-university hospitals, respectively, thought that implementation of a fertility preservation program at a public facility would be desirable. Although most oncologists recognize the importance of providing information on reproductive medicine, the support system for reproductive function and fertility in adolescent and young adult (AYA) generation cancer patients is limited because of the lack of agreement on patient referral. The limited number of referrals in turn limits data collection in the field of oncofertility. Grant: A Health and Labour Sciences Research Grant: H27-Cancer Control-Ippan.

The aim of the present study was to characterize the effect of long-term usage of dienogest, a fourth-generation progestin that possesses progestogen and anti-androgen activities, on the stockpile of oocytes and fertility after administration. Female ICR mice (100 days old) were divided into a dienogest group and a control group. The mice received 16 consecutive subcutaneous injections of 5 mg dienogest dissolved in corn oil or corn oil as a vehicle control every 4 days. The mice treated with dienogest had more total offspring and larger litter sizes after the final administration than the mice treated with the vehicle control. Greater numbers of primordial follicles were detected at both 4 and 80 days after the final administration. No significant differences were found in serum anti-Müllerian hormone concentrations at 4 and 80 days after the final dienogest administration. The ratio of primary to primordial follicles was decreased in 3-day-old newborn ovaries cultured for 4 days with dienogest (10 -7 , 10 -6 and 10 -5 mol/l) compared with ovaries cultured without dienogest. The results of the present study indicate that dienogest suppresses the activation of primordial follicles during its administration and preserves the primordial follicle stockpile and subsequent fertility in mice., (Copyright © 2018 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Objective: To study the effects of adenomyosis on the coagulation and fibrinolysis system during menstruation and the relationship between dysfunction of the coagulation and fibrinolysis system and the symptoms and complications of adenomyosis., Study Design: Concentrations of thrombin-antithrombin complex (TAT) and soluble fibrin (SF) as markers of coagulation, D-dimer (DD) as a marker of both coagulation and fibrinolysis, and plasmin-alpha 2-plasmin inhibitor complex (PIC) as a marker of fibrinolysis in the peripheral blood of eight patients with adenomyosis were measured daily from the first to fifth day of menstruation. Associations between levels of these markers during menstruation and patient characteristics, history of thrombotic disorder, and hemoglobin loss during menstruation were investigated., Results: TAT, SF, DD and PIC increased in 5, 2, 3 and 1 of the 8 patients, respectively. TAT increased in 5 of the 6 patients with an adenomyotic uterus ≥100 cubic centimeters. Patients with elevated DD, SF and/or PIC were among patients with elevated TAT. DD was only increased in 3 patients with a past history of small cerebral infarction or pulmonary thromboembolism and/or hemoglobin loss >2.0g/dl during menstruation. SF was increased only in 2 patients with a past history of cerebral infarction or pulmonary thromboembolism. PIC increased in 1 of the 2 patients with hemoglobin loss >2.0g/dl during menstruation., Conclusion: Adenomyosis patients with a uterus volume ≥100 cubic centimeters are at risk of having an activated coagulation system. These patients, particularly those with elevated SF and DD, may be at risk of thrombotic disorders. Fibrinolysis is activated in a portion of patients with activated coagulation during menstruation. Activated fibrinolysis during menstruation may contribute to menorrhagia in patients with adenomyosis, as only patients with activated fibrinolysis suffered menorrhagia, even though patients with an adenomyotic uterus ≥100 cubic centimeters without activated fibrinolysis did not. These results suggest extensive adenomyosis confers a potential risk of infarction and thrombosis and exacerbates menorrhagia via activation of coagulation and fibrinolysis during menstruation., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Problem: Endometriosis is recognized as a chronic inflammatory disease and is related to immune response. There have been reports that revealed the different distribution of macrophage within the eutopic endometrium of women with endometriosis. Macrophages are functionally polarized into M1 and M2 cell lineages. We studied a difference in the subpopulations of M1 and M2 macrophages within the eutopic endometrium in patients with or without endometriosis to investigate how the eutopic endometrium is stimulated immunologically., Method of Study: Thirty-six patients with endometriosis (endometriosis group) and 37 without endometriosis (non-endometriosis group) were analyzed. Paraffin-embedded endometrial specimens were used for the study. Consecutive sections were used for immunostaining of CD68 (pan-macrophage marker) and CD163 (M2 macrophage marker). Cells positive for each marker were quantified, and the ratio of M2 macrophages in pan-macrophages was calculated., Result: The endometriosis group had a significantly higher number of pan-macrophages than the control group in all phases (P < 0.05). The ratios of M2 macrophages in pan-macrophages were significantly lower in all phases in the endometriosis group (P < 0.05)., Conclusion: The macrophage population slants toward M1 in the endometrium of endometriosis patients. The endometrium appeared to be stimulated by some organelles and/or substances that induce M1 in endometriosis patients., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: To investigate the direct effects of progesterone receptor (PR) agonists on proliferation and apoptosis of human adenomyotic cells., Study Design: Human primary cultures of adenomyotic stromal cells (ASCs) from 24 patients with adenomyosis were co-treated with estradiol (E2) plus the PR agonists, endogenous progesterone (P) or the synthetic progestin dienogest (DNG), which is used to treat endometriosis. In ASCs, anti-proliferative effects and induction of apoptosis were evaluated in the presence or absence of P (10(-8)-10(-6)M) or DNG (10(-8)-10(-6)M) in culture medium containing E2. Cellular proliferation was analyzed with bromodeoxyuridine incorporation and flow cytometry. Apoptosis was detected with annexin V/7-amino-actinomycin D (7-AAD) staining with flow cytometry and cellular caspase 3/7 activity., Results: P and DNG significantly decreased the proportion of cells in the S phase. In addition, both P and DNG increased apoptosis as measured by annexin V-positive/7-AAD -negative cells and caspase 3/7 activity., Conclusions: Both endogenous P and synthetic progestin directly inhibited cellular proliferation and induced apoptosis in human ASCs. These pharmacological features of progestational compounds provide insight into the therapeutic strategy for the treatment of adenomyosis., (Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Follistatin (FST) is an antagonist of activin and related TGFβ superfamily members that has important reproductive actions as well as critical regulatory functions in other tissues and systems. FST is produced as three protein isoforms that differ in their biochemical properties and in their localization within the body. We created FST288-only mice that only express the short FST288 isoform and previously reported that females are subfertile, but have an excess of primordial follicles on postnatal day (PND) 8.5 that undergo accelerated demise in adults. We have now examined germ cell nest breakdown and primordial follicle formation in the critical PND 0.5-8.5 period to test the hypothesis that the excess primordial follicles derive from increased proliferation and decreased apoptosis during germ cell nest breakdown. Using double immunofluorescence microscopy we found that there is virtually no germ cell proliferation after birth in wild-type or FST288-only females. However, the entire process of germ cell nest breakdown was extended in time (through at least PND 8.5) and apoptosis was significantly reduced in FST288-only females. In addition, FST288-only females are born with more germ cells within the nests. Thus, the excess primordial follicles in FST288-only mice derive from a greater number of germ cells at birth as well as a reduced rate of apoptosis during nest breakdown. These results also demonstrate that FST is critical for normal regulation of germ cell nest breakdown and that loss of the FST303 and/or FST315 isoforms leads to excess primordial follicles with accelerated demise, resulting in premature cessation of ovarian function.

Follistatin (FST) is a natural antagonist of activin and related TGFbeta superfamily ligands that exists as three protein isoforms differing in length at the C terminus. The longest FST315 isoform is found in the circulation, whereas the shortest FST288 isoform is typically found in or on cells and tissues, and the intermediate FST303 isoform is found in gonads. We recently demonstrated that the FST isoforms have distinct biological actions in vitro that, taken together with the differential distribution, suggests they may also have different roles in vivo. To explore the specific role of individual FST isoforms, we created a single-isoform FST288-only mouse. In contrast to the neonatal death of FST global knockout mice, FST288-only mice survive to adulthood. Although they appear normal, FST288-only mice have fertility defects including reduced litter size and frequency. Follicles were counted in ovaries from 8.5- to 400-d-old females. Significantly fewer morphologically healthy antral follicles were found in 100- to 250-d FST288-only ovaries, but there were significantly more secondary, primary, and primordial follicles detected at d 8.5 in FST288-only ovaries. However, depletion of this primordial follicle pool is more rapid in FST288-only females resulting in a deficit by 250 d of age and early cessation of reproduction. Superovulated FST288-only females have fewer ovulated eggs and embryos. These results indicate that the FST isoforms have different activities in vivo, that the FST288-only isoform is sufficient for development, and that loss of FST303 and FST315 isoforms results in fertility defects that resemble activin hyperactivity and premature ovarian failure.

CD28 molecule expression on the surface of T cells plays a critical role in upregulation of various cytokines synthesis and T-helper (Th) cell proliferation and differentiation. However aging induces a decrease in CD28 expression and unbalance of Th1/Th2, leading to impairment of Th-cell mediated immune function. The purpose of this study was to assess the effects of moderate exercise training on CD28 expression and the balance of Th1/Th2 cells in elderly people. Forty-eight elderly subjects were assigned to an exercise training group (EXC: 13 males, 15 females; aged 61-76) or a non-exercise control group (CON: 7 males, 13 females; aged 62-79). Subjects in EXC participated in exercise sessions 5-days a week for 6 months. Meanwhile, subjects in CON maintained their normal physical activity levels during the study period. Blood samples were collected before and after the training period. Samples were measured for the number of leukocytes and lymphocytes, as well as for CD3+, CD4+, CD28+CD4+, IFN-gamma+CD4+, IL-4+CD4+ cells. The number of leukocytes, lymphocytes, and CD3+ cells did not change after 6 months in both EXC and CON. The number of CD4+ and CD28+CD4+ cells significantly increased after the training in EXC (P < 0.05), while CON did not show significant changes. In the EXC group, IFN-gamma+CD4+ cell numbers were significantly higher following the training (P < 0.05), but the number of IL-4+CD4+ cells was not changed. In the CON group, there were no significant alterations in IFN-gamma+CD4+ and IL-4+CD4+ cell numbers. In conclusion, moderate exercise training in the elderly is associated with improvement of expression of CD28 on Th cells and Th1/Th2 balances. Therefore, exercise training could up-regulate Th cell-mediated immune functions and be helpful for a decrease in the risk of infections and autoimmune diseases in elderly people.

The influence of age and gender on salivary secretory immunoglobulin A (SIgA) in response to moderate exercise training was studied in 158 elderly subjects. Subjects were assigned to an exercise training group (EXC: 51 males, 74 females) or a non-exercise control group (CON: 11 males, 22 females). The subjects in each group were separated into four age-gender subgroups (60-69-yr-old males, over 70-yr-old males, 60-69-yr-old females, over 70-yr-old females) and compared by age and gender. Subjects in EXC participated in exercise sessions 5-days a week for 6 months. Saliva samples were collected both before and after the study period. The SIgA secretion rates were significantly increased after training (p < 0.05) in all the age-gender subgroups of EXC (60-69 males: 41%, over 70 males: 55%, 60-69 females: 40%, over 70 females: 38%); no age- or gender-related differences were observed. On the other hand, none of the age-gender subgroups of CON showed significant changes in the SIgA secretion rate; also, there were no age- or gender-related differences. In conclusion, enhancement of mucosal immune function following regular moderate exercise training occurs in elderlies in their 60s and over 70 years, and in both, males and females.

Aim: We aimed to examine the effect of Coenzyme Q10 (CoQ10) supplementation on the exhaustive exercise-induced injury and oxidative stress in skeletal muscle and liver., Methods: Rats were divided into four groups: rest group [control (Con)-Rest; n = 6)], exercise group (Con-Ex; n = 6), rest group with CoQ10 supplement (CoQ10-Rest; n = 6), and exercise group with CoQ10 supplement (CoQ10-Ex; n = 6). The exercise groups were run on a treadmill until exhaustion. The CoQ10 supplemented groups received an oral administration of CoQ10 (300 mg kg(-1), 4 weeks). After 4 weeks, total CoQ concentration, creatine kinase (CK), glutamic-oxaloacetic transaminase (GOT), malondialdehyde (MDA), scavenging activity against reactive oxygen species [ROS; superoxide anions (O2*-) and hydroxyl radicals (HO*)] were measured., Results: Total CoQ concentration in plasma, slow-twitch muscles (soleus and gastronemius deep portion), and liver were significantly increased by CoQ10 supplementation. Plasma CK was significantly higher in Con-Ex compared with Con-Rest, whereas there was no difference between CoQ10-Rest and CoQ10-Ex. There were no significant differences in muscle MDA in each group. Plasma GOT and liver MDA in exercise groups were significantly higher than that of rest groups, but not significantly different between CoQ10 supplemented groups and control groups. CoQ10 supplementation was not able to favorably influence ROS scavenging activity in skeletal muscle and liver., Conclusions: These data indicated that CoQ10 supplementation increased total CoQ concentration in the slow-twitch muscles, and was useful for reducing exhaustive exercise-induced muscular injury by enhancing stabilization of muscle cell membrane.